Properties ofV max block of INa-mediated action potentials during combined application of antiarrhythmic drugs in cardiac muscle

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Abstract
TotalVmax blockade increased in response to the addition of quinidine (1×10−5 mol/l), lidocaine (3×10−5 or 3×10−4 mol/l) or prajmalium (2.5×10−5 mol/l) to a propafenone-containing (5×10−6 mol/l) medium. This intensification originated from an increase of both tonic (rested-state) and phasic (use-dependent)Vmax blockade when kinetically similar drugs such as propafenone and quinidine may interact simultaneously with Na+ channels and, thus, resembles the effects of a rise in drug concentration. Accordingly, the development kinetics of phasicVmax blockade were accelerated but block relaxation kinetics remained unaffected. Intensification of totalVmax blockade induced by combining propafenone with the kinetically different lidocaine resulted exclusively from an increase of tonic blockade at driving rates between 0.2 and 1 Hz. Steady state phasicVmax blockade remained within this frequency range unchanged or decreased depending on whether the lidocaine concentration in the propafenone-containing medium was low or high. Although the strength of first beat phasicVmax block went up in both cases, the propafenone-induced fraction declined in the presence of the higher lidocaine concentration. Development and relaxation kinetics of phasicVmax blockade became modified when Na+ channels were exposed to a mixture of kinetically different drugs, propafenone plus lidocaine or propafenone plus prajmalium. Instead of a single exponential time course, development and removal of phasicVmax blockade consisted of two different components. The biexponential time course of phasic block onset in propafenone plus prajmalium, the biexponential time course of phasic block relaxation in propafenone plus lidocaine and the interference of one drug with the blocking action of another strongly suggest a Na+ channel-associated drug receptor. Propafenone and lidocaine very probably find a common target which might bear a single or two allosterically linked binding sites.